1. FIELD OF THE INVENTION
This invention relates to novel N.sup.4 -acyloxy-2,2'-cyclocytidines and N.sup.4,3',5'-tri-O-acyl-2,2'-cyclocytidines which decrease the total packed volume ratio (T/C%) with respect to ascitic form of Sarcoma 180 in small animals, and have an effect of prolonging their lives.
2. DESCRIPTION OF THE PRIOR ART
2,2'-Cyclocytidine is known to be useful as an antileukemic agent having few side-effects and has been clinically evaluated in many countries (e.g., as disclosed in Y. Sakai et al., Japan J. Clin. Oncol., 2, 57 (1972)), and a method for treating leukemia is disclosed in German Patent (DAS) No. 2,159,181 and French Pat. No. 2,138,603 (both corresponding to U.S. patent Ser. No. 598,897, filed July 24, 1975).
A wide variety of 2,2'-cyclocytidine derivatives have also been disclosed in the art. For example, British Pat. No. 1,325,798 (corresponding to U.S. patent application Ser. No. 75,272, filed Sept. 24, 1970) discloses 2,2'-anhydro-ara-cytidine derivatives having a 5'-O-acyl group and a 4-imino salt group which are said to have anti-viral, antitumour and immunosuppressive activities. Japanese Patent Application (OPI) No. 16,481/1972 (corresponding to U.S. patent application Ser. No. 110,312, filed Jan. 27, 1971) discloses a method of preparation of 3',5'-di-O-acyl-aracytidines having excellent immunosuppressive, antitumour and anti-leukemic activities by acylating 2,2'-cyclocytidine to introduce an aromatic acyl group and through 3'-O-, 5'-O- and N.sup.4 -triacyl-cyclocytidine as an intermediate. U.S. Pat. No. 3,709,874 discloses 1-.beta.-D-arabino-furanosyl cytosine derivatives having antiviral and cytotoxic activities.
Some cyclocytidine derivatives, i.e., N.sup.4 -substituted-2,2'-cyclocytidines, have been reported to have an anti-leukemic activity in experimental animals approximately equivalent to or higher than that of the parent compound, 2,2'-cyclocytidine (e.g., as disclosed in Kanai, et al., J. Med. Chem., Vol. 17, page 1076 (1974)). Typical examples of such N.sup.4 -substituted-2,2'-cyclocytidines are N.sup.4 -hydroxy-2,2'-cyclocytidine, N.sup.4 -hydroxy-5'-acetyl-2,2'-cyclocytidine, N.sup.4 -O-alkyl-2,2'-cyclocytidine, etc., as disclosed in Japanese Patent Application (OPI) No. 23788/1973, in British Pat. No. 1,386,334 and in French Pat. No. 2,199,460, N.sup.4 -hydroxy-3'-O-benzoyl or -O-acetyl, -O-palmitoyl derivatives, etc., of 2,2'-cyclocytidine as disclosed in Japanese Patent Application (OPI) No. 88095/1975, N.sup.4 -hydroxy-5'-O-benzoyl or -O-acetyl, -O-adamantoyl derivatives, etc., of 2,2'-cyclocytidine as disclosed in Japanese Patent Application (OPI) No. 88097/1975, N.sup.4 -hydroxy-3',5'-di-O-acetyl or di-O-stearoyl, di-O-hexanoyl derivatives, etc., of 2,2'-cyclocytidine as disclosed in Japanese Patent Application (OPI) No. 88096/1975 and in British Pat. No. 1,480,120.